Cerebrospinal fluid (CSF), antigens, and antigen-presenting cells drain from the central nervous system (CNS) into lymphatic vessels near the cribriform plate and dura, yet the role of these vessels during stroke is unclear. Using a mouse model of ischemic stroke, transient middle cerebral artery occlusion (tMCAO), we demonstrate stroke-induced lymphangiogenesis near the cribriform plate, peaking at day 7 and regressing by day 14. Lymphangiogenesis is restricted to the cribriform plate and deep cervical lymph nodes and is regulated by VEGF-C/VEGFR-3 signaling. The use of a VEGFR-3 inhibitor prevented lymphangiogenesis and led to improved stroke outcomes at earlier time points, with no effects at later time points. VEGF-C delivery after tMCAO did not further increase post-stroke lymphangiogenesis, but instead induced larger brain infarcts. Our data support the damaging role of VEGF-C acutely and a pro-angiogenic role chronically. This nuanced understanding of VEGFR-3 and VEGF-C in stroke pathology advises caution regarding therapeutic VEGF-C use in stroke.
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3 February 2025
Article|
December 12 2024
Dual role of vascular endothelial growth factor-C in post-stroke recovery
Yun Hwa Choi
,
Yun Hwa Choi
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Department of Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
2
Waisman Center, University of Wisconsin-Madison
, Madison, WI, USA
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Martin Hsu
,
Martin Hsu
*
(Investigation)
3Department of Microbiology and Immunology,
University of North Carolina, Chapel Hill
, Chapel Hill, NC, USA
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Collin Laaker
,
Collin Laaker
*
(Formal analysis, Investigation, Visualization, Writing - original draft, Writing - review & editing)
4
Neuroscience Training Program, University of Wisconsin-Madison
, Madison, WI, USA
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Jenna Port
,
Jenna Port
(Formal analysis, Investigation)
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
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Kristóf G. Kovács
,
Kristóf G. Kovács
(Investigation, Writing - review & editing)
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
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Melinda Herbath
,
Melinda Herbath
(Formal analysis, Investigation, Methodology, Visualization, Writing - review & editing)
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
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Heeyoon Yang
,
Heeyoon Yang
(Data curation)
6
College of Agricultural and Life Sciences, University of Wisconsin-Madison
, Madison, WI, USA
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Peter Cismaru
,
Peter Cismaru
(Data curation, Investigation, Methodology)
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
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Alexis M. Johnson
,
Alexis M. Johnson
(Investigation, Writing - review & editing)
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
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Bailey Spellman
,
Bailey Spellman
(Investigation)
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
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Kelsey Wigand
,
Kelsey Wigand
(Conceptualization, Formal analysis, Investigation, Methodology, Resources)
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
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Matyas Sandor
,
Matyas Sandor
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Validation, Writing - review & editing)
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
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Zsuzsanna Fabry
(Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Validation, Visualization, Writing - review & editing)
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
Correspondence to Zsuzsanna Fabry: [email protected]
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Yun Hwa Choi
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing
1Department of Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
2
Waisman Center, University of Wisconsin-Madison
, Madison, WI, USA
3Department of Microbiology and Immunology,
University of North Carolina, Chapel Hill
, Chapel Hill, NC, USA
Collin Laaker
Formal analysis, Investigation, Visualization, Writing - original draft, Writing - review & editing
*
4
Neuroscience Training Program, University of Wisconsin-Madison
, Madison, WI, USA
Jenna Port
Formal analysis, Investigation
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
Kristóf G. Kovács
Investigation, Writing - review & editing
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
Melinda Herbath
Formal analysis, Investigation, Methodology, Visualization, Writing - review & editing
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
Heeyoon Yang
Data curation
6
College of Agricultural and Life Sciences, University of Wisconsin-Madison
, Madison, WI, USA
Peter Cismaru
Data curation, Investigation, Methodology
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
Alexis M. Johnson
Investigation, Writing - review & editing
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
Bailey Spellman
Investigation
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
Kelsey Wigand
Conceptualization, Formal analysis, Investigation, Methodology, Resources
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
Matyas Sandor
Conceptualization, Data curation, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Validation, Writing - review & editing
5Department of Pathology and Laboratory Medicine,
University of Wisconsin-Madison
, Madison, WI, USA
Correspondence to Zsuzsanna Fabry: [email protected]
*
M. Hsu and C. Laaker contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
Received:
October 05 2023
Revision Received:
September 25 2024
Accepted:
November 11 2024
Online ISSN: 1540-9538
Print ISSN: 0022-1007
Funding
Funder(s):
University of Wisconsin Carbone Cancer Center
- Award Id(s): P30CA014520
Funder(s):
National Institutes of Health
- Award Id(s): NS108497,NS103506,HL128778
Funder(s):
Neuroscience Training Program
- Award Id(s): T32-NS105602
Funder(s):
American Heart Association
- Award Id(s): 915125
© 2024 Choi et al.
2024
Choi et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
This work is licensed under a
Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License
.
J Exp Med (2025) 222 (2): e20231816.
Article history
Received:
October 05 2023
Revision Received:
September 25 2024
Accepted:
November 11 2024
Citation
Yun Hwa Choi, Martin Hsu, Collin Laaker, Jenna Port, Kristóf G. Kovács, Melinda Herbath, Heeyoon Yang, Peter Cismaru, Alexis M. Johnson, Bailey Spellman, Kelsey Wigand, Matyas Sandor, Zsuzsanna Fabry; Dual role of vascular endothelial growth factor-C in post-stroke recovery. J Exp Med 3 February 2025; 222 (2): e20231816. doi: https://doi.org/10.1084/jem.20231816
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